Type 2 diabetes drug Kombiglyze XR (saxagliptin and metformin) may increase the risk of heart failure and other cardiovascular injuries in some patients.

Studies have shown that patients with a history of cardiovascular issues have a 27% greater chance of being hospitalized for heart failure while taking Kombiglyze XR or its sister drug Onglyza (saxagliptin). Based on these findings, the U.S. Food and Drug Administration (FDA) now requires manufacturer AstraZeneca to include a warning on the drugs’ labeling that patients may suffer from heart failure or other cardiovascular injuries.

How Does Kombiglyze XR Work?

Kombiglyze XR treats type 2 diabetes by helping the body to produce more insulin and respond better to insulin, as well as reduce the amount of glucose the body produces.

Kombiglyze XR and Onglyza are part of a class of drugs known as incretin mimetics which includes Byetta, Victoza, and Januvia. These drugs mimic a hormone in the body that triggers the body to produce more insulin.

Within that class, Onglyza is part of a smaller class of dipeptidyl peptidase-4 (DPP-4) inhibitors. These drugs target an enzyme (DPP-4) that destroys a hormone in the gut called GLP-1. This is important for patients with type 2 diabetes because GLP-1 stimulates the pancreas to produce insulin—essential to regulating blood glucose levels. By targeting DPP-4, drugs like Onglyza allow for the body to retain GLP-1 for longer periods of time, and ultimately produce higher levels of insulin in the body.

Kombiglyze has a similar effect on patients but since it combines Onglyza (saxagliptin) with metformin, it fights high blood sugar in other ways as well.

Metformin, made by Bristol-Myers, is part of a group of drugs known as biguanides. These drugs do not help the body to produce more insulin, but instead, help the body to respond better to insulin. They also help reduce the amount of blood sugar that is created by the liver and absorbed by the intestines.

As a DPP-4 inhibitor and metformin combination drug, Kombiglyze treats type 2 diabetes by helping the body to produce more insulin and respond better to insulin, as well as reduce the amount of glucose the body produces. Janumet, produced by Merck, works similarly by combining Januvia (sitagliptin) with metformin.

Does Kombiglyze XR Put Patients at a Greater Risk of Heart Failure?

Participants who were given Onglyza and Kombiglyze XR had a 27% greater chance of being hospitalized for heart failure compared to those who were given a placebo.

Patients taking Kombiglyze XR and Onglyza may have a greater chance of being hospitalized for heart failure, according to the results of the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus, or SAVOR trial, funded by AstraZeneca and Bristol-Myers.

The study followed more than 16,000 participants with a history of heart problems over a two-year period. Half were blindly given Onglyza or Kombiglyze XR, and the other half received a placebo.

Participants who were given Onglyza and Kombiglyze had a 27% greater chance of hospitalization for heart failure compared to those who were given a placebo. Participants also had a significant risk of all-cause mortality while taking these drugs.

After reviewing the SAVOR results, 14 out of 15 FDA panelists voted to require Onglyza and Kombiglyze XR to include a warning that the drugs had a risk of cardiac injury. In 2016, the FDA warned that Kombiglyze may cause heart failure in some patients, particularly in individuals with a history of heart disease and kidney disease.

But why do these drugs have this effect? Scientists still aren’t sure. One theory is that they may affect the heart rate and that there may even be GLP-1 receptors in the atrium of the heart, which the drugs may be affecting.

“If you do have a patient with heart failure and you want to add this drug—and this drug does have a lot of important [beneficial] effects (e.g., doesn’t cause weight gain, doesn’t cause hypoglycemia, etc.)—you should follow your patient closely,” recommended Dr. Raz, one of the leading researchers in the SAVOR trial.

How Does the SAVOR Trial Compare to Other Studies?

After the publication of the SAVOR results, a study published in the British Medical Journal (BMJ) further examined the association between DPP-4 inhibitors and heart failure. They looked at the results from clinical trials published on Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov through June 25, 2015.

Researchers concluded that the risk of heart failure from these drugs was still unclear since the only published results were based on studies with short follow-up periods.

Despite this, researchers cautioned, “Both randomized controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.”

What Other Side Effects Does Kombiglyze XR Cause?

Pancreatitis, Pancreatic Cancer

In some cases, patients can experience a 50% enlargement of their pancreas while taking Kombiglyze XR.

In 2011, the agency issued a warning for pancreatitis. In a 2013 safety communication, they cautioned that Kombiglyze’s effect on the pancreas could be more serious as they found pre-cancerous cellular changes in the pancreas of some patients taking the drug. These cellular changes, they cautioned, could result in pancreatic cancer.

It’s still unclear how incretin mimetic drugs cause pancreatitis, but experts believe it may be related to pancreatic enlargement experienced by some patients. In some cases, patients can experience a 50% enlargement of their pancreas while on these drugs. Enlargement of the pancreas causes compression and inflammation which can lead to pancreatitis.

Scientists initially got the idea for the first incretin mimetic drug, exenatide, from the desert-based Gila Monster. The lizard rarely eats, sometimes with month-long gaps in between meals, but when it does, the polypeptides found in its saliva help its pancreas rapidly grow to accommodate food.

BMJ scientists say that it isn’t surprising that incretin mimetics like Onglyza and Kombiglyze XR cause the pancreas to enlarge in humans since it has this effect in the Gila Monster. In the publication of their results, BMJ researchers asked the pharmaceutical company why patients and doctors weren’t notified of the health risks of these drugs sooner.

Lactic Acidosis

Metformin has a boxed warning for lactic acidosis—the highest warning the FDA bestows.

Lactic acidosis is another known side effect of Kombiglyze XR, which the FDA has officially issued a warning for. Lactic acidosis is when lactic acid builds up in the bloodstream, resulting in low pH which can be serious and even fatal.

Kombiglyze has a risk of causing lactic acidosis because of the presence of metformin. Metformin has a boxed warning for the condition—the highest warning the FDA bestows. Patients with a history of kidney, liver, or heart problems are particularly at risk of suffering from lactic acidosis.

Severe Joint Pain

After receiving multiple adverse event reports from patients complaining of joint pain, the FDA issued a warning in 2015. Some patients experienced joint pain that was so severe that it required hospitalization.

Have Lawsuits Been Filed Against AstraZeneca?

AstraZeneca and Bristol-Myers, who previously manufactured Onglyza and Kombiglyze XR prior to selling them to AstraZeneca, face dozens of lawsuits alleging that the manufacturers failed to perform adequate safety tests on the drugs.

Individuals who suffered from heart failure or other cardiovascular injuries, such as congestive heart failure or myocardial infarction, may be eligible for a lawsuit against AstraZeneca and Bristol-Myers. To learn more about lawsuit eligibility, contact us for a free, no-obligation legal review.

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